Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT.

BACKGROUND: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. DESIGN: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. SETTING: The trial was conducted in 121 UK primary and secondary care sites. PARTICIPANTS: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year. INTERVENTIONS: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. PRIMARY OUTCOME: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. RESULTS: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. LIMITATIONS: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. CONCLUSION: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. FUTURE WORK: To promote consideration of the findings of this trial in national and international COPD guidelines. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that cannot be cured. The main symptom is shortness of breath on exertion. In the UK, about 1.2 million people have COPD. It is a major cause of death and costs the NHS > £1B a year. Sudden 'flare-ups' of symptoms often need emergency treatment, shorten life expectancy and reduce people's ability to get on with their lives. Theophylline is a drug that has been around for decades. In the past, it was used in high doses to treat COPD by opening up airways. However, its benefits were limited and it often caused unpleasant side effects. High-dose theophylline has been replaced by drugs administered by inhalers, such as inhaled corticosteroids (ICSs). Recent work in the laboratory and in animal models suggests that, at low dose, theophylline could make ICSs work better in COPD with none of the side effects of high-dose theophylline. The Theophylline With Inhaled CorticoSteroid (TWICS) trial tested whether or not adding low-dose theophylline reduces flare-ups in people with COPD taking ICSs. A total of 1578 people with COPD from 121 centres all over the UK took part. Participants were randomly divided into two groups: one group took low-dose theophylline and the other took dummy placebo pills. Participants were asked to attend visits at 6 and 12 months. A total of 791 participants were prescribed low-dose theophylline and 787 were prescribed dummy placebo pills. Although not everyone took the tablets for a whole year, it was possible to count the number of flare-ups in 98% of those taking part. In total, there were 3430 flare-ups. On average, the people taking low-dose theophylline had 2.24 flare-ups and the people taking placebo had 2.23 flare-ups. Overall, the trial showed that, for people with COPD, taking low-dose theophylline on top of steroid inhalers makes no real difference.

Behavioural activation versus guided self-help for depression in adults with learning disabilities: the BeatIt RCT.

BACKGROUND: Depression is the most prevalent mental health problem among people with learning disabilities. OBJECTIVE: The trial investigated the clinical effectiveness and cost-effectiveness of behavioural activation for depression experienced by people with mild to moderate learning disabilities. The intervention was compared with a guided self-help intervention. DESIGN: A multicentre, single-blind, randomised controlled trial, with follow-up at 4, 8 and 12 months post randomisation. There was a nested qualitative study. SETTING: Participants were recruited from community learning disability teams and services and from Improving Access to Psychological Therapies services in Scotland, England and Wales. PARTICIPANTS: Participants were aged ≥ 18 years, with clinically significant depression, assessed using the Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities. Participants had to be able to give informed consent and a supporter could accompany them to therapy. INTERVENTIONS: BeatIt was a manualised behavioural activation intervention, adapted for people with learning disabilities and depression. StepUp was an adapted guided self-help intervention. MAIN OUTCOME MEASURES: The primary outcome measure was the Glasgow Depression Scale for people with a Learning Disability (GDS-LD). Secondary outcomes included carer ratings of depressive symptoms and aggressiveness, self-reporting of anxiety symptoms, social support, activity and adaptive behaviour, relationships, quality of life (QoL) and life events, and resource and medication use. RESULTS: There were 161 participants randomised (BeatIt, n = 84; StepUp, n = 77). Participant retention was strong, with 141 completing the trial. Most completed therapy (BeatIt: 86%; StepUp: 82%). At baseline, 63% of BeatIt participants and 66% of StepUp participants were prescribed antidepressants. There was no statistically significant difference in GDS-LD scores between the StepUp (12.94 points) and BeatIt (11.91 points) groups at the 12-month primary outcome point. However, both groups improved during the trial. Other psychological and QoL outcomes followed a similar pattern. There were no treatment group differences, but there was improvement in both groups. There was no economic evidence suggesting that BeatIt may be more cost-effective than StepUp. However, treatment costs for both groups were approximately only 4-6.5% of the total support costs. Results of the qualitative research with participants, supporters and therapists were in concert with the quantitative findings. Both treatments were perceived as active interventions and were valued in terms of their structure, content and perceived impact. LIMITATIONS: A significant limitation was the absence of a treatment-as-usual (TAU) comparison. CONCLUSIONS: Primary and secondary outcomes, economic data and qualitative results all clearly demonstrate that there was no evidence for BeatIt being more effective than StepUp. FUTURE WORK: Comparisons against TAU are required to determine whether or not these interventions had any effect. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09753005. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 53. See the NIHR Journals Library website for further project information.

A parallel group randomised open blinded evaluation of Acceptance and Commitment Therapy for depression after psychosis: Pilot trial outcomes (ADAPT).

BACKGROUND: Depression is one of the major contributors to poorer quality of life amongst individuals with psychosis and schizophrenia. The study was designed as a Pilot Trial to determine the parameters of a larger, definitive pragmatic multi-centre randomised controlled trial of Acceptance and Commitment Therapy for depression after psychosis (ACTdp) for individuals with a diagnosis of schizophrenia who also meet diagnostic criteria for major depression. METHODS: Participants were required to meet criteria for schizophrenia and major depression. Blinded follow-ups were undertaken at 5-months (end of treatment) and at 10-months (5-months posttreatment). Primary outcomes were depression as measured by the Calgary Depression Scale for Schizophrenia (CDSS) and the Beck Depression Inventory (BDI). RESULTS: A total of 29 participants were randomised to ACTdp + Standard Care (SC) (n=15) or SC alone (n=14). We did not observe significant differences between groups on the CDSS total score at 5-months (Coeff=-1.43, 95%CI -5.17, 2.32, p=0.45) or at 10-months (Coeff=1.8, 95%CI -2.10, 5.69, p=0.36). In terms of BDI, we noted a statistically significant effect in favour of ACTdp+SC at 5-months (Coeff=-8.38, 95%CI -15.49, -1.27, p=0.02) but not at 10-months (Coeff=-4.85, 95%CI -12.10, 2.39, p=0.18). We also observed significant effects on psychological flexibility at 5-months (Coeff=-8.83, 95%CI -14.94, -2.71, p<0.01) but not 10-months (Coeff=-4.92, 95%CI -11.09, 1.25, p=0.11). IMPLICATIONS: In this first RCT of a psychological therapy with depression as the primary outcome, ACT is a promising intervention for depression in the context of psychosis. A further large-scale definitive randomised controlled trial is required to determine effectiveness. TRIAL REGISTRATION: ISRCTN: 33306437.